My mouse has two daddies

This is awesome news. Biologists have figured out how to enable two male mice to have babies together, with no genetic contribution from a female mouse. I, for one, look forward to our future gay rodent overlords.

It was a clever piece of work. Getting progeny from two male parents has a couple of difficulties. One is that you need an oocyte, which is a large, specialized, complex cell type, and males don't make them. Not at all. You can tear a boy mouse to pieces looking for one, and you won't find a single example—they're a cell found exclusively in female ovaries.

Now you might think that all we'd have to do is grab one from a female mouse, throw out its nuclear contents, and inject a male nucleus into it, but that doesn't work, either. The second problem is that during the maturation of the oocyte, the DNA has to be imprinted, that is, given a female-specific pattern of activation and inactivation of genes. If that isn't done, there will be a genetic imbalance at fertilization, and development will be abnormal. What we need to be able to do is grow an oocyte progenitor with male DNA in a female ovary.

So that's what was done, and here's how.

Start with Father #1, whose cells all contain an X and a Y chromosome. Connective tissue cells were extracted from the mouse (in this case, an embryo), and then reprogrammed by viral transduction with modified copies of the genes Pou5f1, Sox2, Klf4, and Myc. This step produces induced pluripotent stem cells (iPS cells), or cells that have the ability to develop into all (probably) of the tissues of the body. These cells are then grown in a dish.

The next step is to give Father #1's cells a sex change operation. This turns out to be trivial: in culture, cells can spontaneously lose a chromosome by non-disjunction, and 1-3% of the cells will lose their Y chromosome, and convert to X0. No Y chromosome means it is now a functionally female cell.

There is a significant difference between humans and mice here. Sometimes (about 1 in 5,000 births) humans are born with only one X chromosome, a condition called Turner syndrome. These individuals appear to be entirely normal females, except for some minor cosmetic differences, an unfortunate predisposition to a few problems like heart disease, and of particular relevance here, are also sterile. Mice are different: Turner syndrome mice are fertile. Apparently, mice have a god-given edge in the gay reproduction race.

Once a population of Father #1's cells that are X0 are identified, they are then injected into a female mouse blastocyst to produce a chimera, an embryo with a mix of host cells (which are genetically XX) and donor cells (which are X0). That they're mixed together in the resulting offspring doesn't matter; it may be a callous way of looking at it, but the only purpose of the host XX cells is to provide a female mouse environment to house Father #1's X0 cells that end up in the ovaries.

That's the result of all this tinkering: a female mouse is born with a subset of Father #1's reprogrammed cells nestled in her ovaries, where they mature in a female body and differentiate into oocytes. The oocytes divide by meiosis, producing egg cells that contain either one X chromosome, or no sex chromosome at all (0).

Finally, Father #2 comes into the picture. Father #2 is an ordinary male, with testes containing cells that go through meiosis and mature into ordinary sperm containing either one X chromosome or one Y chromosome. These sperm are used to fertilize eggs from the chimeric female, which, by all the shenanigans describe above, are derived from Father #1. Both male (XY) and female (X0) progeny ensue. That this actually occurred was thoroughly confirmed by testing the progeny for genetic markers from both fathers…and it's true. The only genetic contributions were from the dads, and nothing from the host mother.

Now you may be sitting at home with your dearly beloved gay partner and wondering whether you will be able to have babies together someday. Or perhaps you're a narcissistic man sitting at home alone, thinking you'd like to have babies with yourself, if only you could convince a few of your cells to make eggs (this is another possibility: there is no barrier to this technique being applied in cases where Father #1 is also Father #2, except that it is incestuous to the max). I expect it will be possible someday, but it isn't right now. There are a few obstacles to doing this in humans.

1. We haven't worked out that genetic reprogramming trick for humans yet, so we don't have a technique for producing pluripotent stem cells from your somatic cells. Give it time, though, and keep funding adult stem cell research, and it'll happen.

   Also note the rule of unintended consequences. The fundy fanatics have been anti-embryonic stem cell research for years, and one of their tactics has been to insist that adult stem cell research is far more important. In the long run, it is…and oh, look what we'll be able to do!

2. The reprogramming trick involves viral transfection, the insertion of mutant copies of a few specific genes. This is probably not desirable. All kids are mutant anyway, but this is adding a specific, constant kind of mutation to all of the individuals produced by this method.

3. It still requires a woman, and a woman who has been embryonically modified as a blastocyst at that. Did you know women have rights, including the right to not be a vessel for a scientific experiment? It's true. They also take years and years to grow to sexual maturity, so even if you got started right now it would be a dozen years before she started making oocytes for you, and by the way, she'd inform you that she only produces eggs for herself, not you.

   There may be ways around this, but the techniques aren't here yet. To produce eggs, we really don't need the whole woman, just the ovary: another goal of stem cell research is to regrow organs from cells in a dish, for instance to build a new heart or pancreas for transplantation. Consider ovaries on the list of organs.

4. That difference between mice and humans, that X0 mice are fertile while X0 women are not, seems like a serious problem. We apparently need the pair of X chromosomes working together to provide the correct gene dosage for normal maturation of the egg. It just means that we need to add an extra step to the procedure for people, though: transfer by injection an extra X chromosome from a donor cell from Father #1 to the X0 cells, producing a composite XX cell derived entirely from a male.

5. The fundies will go raving apeshit bonkers. So what else is new?

6. OK, there are also some serious ethical concerns that would need to be worked out, independent of the Bible-thumping theocratic sex police. As you can see from the recipe above, this is a procedure that involves extensive manipulation of embryos, almost all of it experimental, and the end result is…a baby. We should be conscientious in our care in any procedure that can produce human beings, especially if there is risk of producing damaged human beings. This can also only be categorized as a kind of expensive luxury treatment, and it's difficult to justify such elaborate work for solely egotistical gratification. Especially for you, nerd-boy masturbating alone at home. (But learning more about the mechanisms of reproduction is more than enough to justify this work in mice, at least).

Wait…all this is just for male gay couples. What about nurturing lesbians who want to have children together? That has another tricky problem: you need a Y chromosome to induce normal sperm differentiation, and lesbian couples don't have any of those. At all. They're going to have to go to a male donor for a genetic contribution, diluting the purity of the genetic side of the procedure. However, that has a technology in the works to help out already: see obstacle #4 above. We'll have to isolate iPS cells from Mother #1, inject a donor Y chromosome into them, cultivate chimeric male (or chimeric testis in a dish) to produce sperm, and then fertilize eggs from Mother #2 with the Mother #1-derived sperm. Any sons produced by this procedure would have three parents, Mother #1, Mother #2, and the Male Donor who provided the Y chromosome, and only the Y chromosome. Any daughters, though, would only have two parents: Mother #1 and Mother #2.

Isn't reproductive biology fun? It's the combination of exciting science with terrifyingly deep social implications.

Deng JM, Satoh K, Chang H, Zhang Z, Stewart MD, Wang H, Cooney AJ, Behringer RR (2010) Generation of viable male and female mice from two fathers. Biology of Reproduction DOI:10.1095/biolreprod.110.088831.